The present invention relates to novel synthesis of γ-carbolines. More specifically, the present invention provides for synthesis of functionlized γ-carboline derivatives.
β-Carbolines, pyrido[3,4-b]indoles, are of interest to the pharmaceutical industry due to their close relationship with natural products such as tryptophan as well as their numerous reported biological activities. Through the years, a number of reports have shown that γ-carbolines, pyrido[4,3-b]indoles, also possess similar biological activities. Several substituted γ-carbolines have been synthesized and examined in a series of in vitro and in vivo pharmacological tests and have been demonstrated antipsychotic, antibiotic, antitumor and other related activities.
There exists no general efficient synthetic route that allows for the formation of highly functionalized γ-carbolines, especially those that contain substituents in the 1- and 4-positions. Of the methods reported, the most widely used for γ-carboline formation is the Fischer synthesis, which often fails completely, or proceeds in low yields unless forcing thermal conditions are used or an activated pyridine ring is employed. An alternative approach is the Grabe-Ullman synthesis and subsequent modifications. This reaction involves the preparation of the phenyl-substituted triazolopyridine followed by elimination of nitrogen upon thermal degradation at temperatures ranging between 190° C. and 500° C. Microwave irradiation has also proven successful on several substrates. Likewise, the formation of a small series of γ-carbolines has been reported by the ring closure of internally generated 2-nitrosobiphenyls synthesized in situ. This reaction proceeds in moderate yields; however, the products are limited to alkyl substituted carbolines. Many of these previously reported methods requiring intramolecular cyclization, proceed in low yields, are limited to non-functional substrates, or involve extreme thermal conditions.
The formation of the desired γ-carbolines in several cases, were byproducts formed while attempting to synthesize the more notable β-carbolines. A unique three-step γ-carboline synthesis employing 4-chloropyridine and o-phenylenediamine in a catalytic palladium (II) coupling reaction was developed while two researchers, Robinson and Thornley, were attempting to synthesize β-carbolines.
Likewise, the intramolecular coupling of a boronic acid with o-fluoroiodopyridine by a Suzuki-type reaction employing a Pd (0) species has been reported. Although an efficient conversion, it involves the synthesis of specialty starting materials, and examples are few in number. The authors reported that the overall three-step process is limited to non-acid-sensitive substrates.
More recently, a novel palladium-catalyzed iminoannulation of internal alkynes was developed. This unique method allows the introduction of functionality into both the 3- and 4-positions of γ-carbolines. Additionally, Larock's group has shown that 3-substituted γ-carbolines, some of which possess 4-annularization, are readily available by a novel palladium/copper catalyzed cyclization reaction of intramolecular or terminal alkynyl indoles. These products have been compared to carbolines which act as cardiovascular agents or as 5-HT3 receptor antagonists. Because of these recent advances and the importance of this class of compounds, needed is a general synthesis and novel approach to afford the complimentary series of γ-carbolines that are substituted in the 1- and 4-positions.
One possible precursor to β-carbolines is through the corresponding tetrahydro-β-carboline and subsequent derivatives. Molecules of this class have recently shown potential for multi drug resistance. The most noted method of synthesis of such proceeds via the Pictet-Spengler synthesis, which condenses tryptamine, a 3-aminomethylindole, with a variety of aldehydes. A simple method to afford the isomeric substituted terahydro-γ-carbolines is lacking even though these compounds are also predicted to exhibit multidrug resistance.
The lack of commercially available 3-aminomethyl indoles, or the facile synthesis of these has hindered the synthesis of the corresponding γ-carbolines. This provides an additional driving force for the development of a method to afford a large selection of functionalized γ-carbolines. A methodology is desirable which allows ease in control of substituents, especially in the 1-position and 4-position, thus creating compounds likely to exhibit desirable pharmacological and biological effects.